Bone marrow stromal cell factor production appears to be a critical aspect of regulating in vivo hemolymphopoiesis. The long-term objective of this grant is to define the nature of stromal derived growth factors both from murine (and human) species involved in the regulation of hemopoiesis with a particular emphasis on actions on early multilineage, stem cells. The specific aims involve the study of the nature of hemolymphopoietic growth factors produced by isolated murine myeloid and lymphoid long term culture adherent cells and the effects of growth factor production of exposure to various inducers including lithium, lectins, phorbol esters, interleukin-l, endotoxin, calcium ionophores and different accessory cells. The growth factors are to be characterized by bioassay, biochemistry and mRNA production and stability. Control of stromal growth factor production will also be assessed at the mRNA level with long-term goals of evaluating possible DNA binding proteins or transacting factors controlling growth factor production. We also plan to assess the role of local conditions in regulating growth factor production from "lymphoid" stroma and "myeloid'' marrow stroma. These studies will address a full evaluation of the nature of the adherent cells in murine myeloid (Dexter) and lymphoid (Whitlock-Witte) long-term marrow cultures and directly assess whether or not two major candidate stromal regulatory cells, a macrophage and the alkaline phosphatase positive preadipocyte fibroblasts, derive from a common progenitor cell. Lastly, studies are designed to address an in vivo model of endotoxin myeloid stimulation attempting to understand the potential role of early acting growth factors in this model. These studies should lead to a more complete understanding of the regulation of early myeloid and lymphoid stem cells and may lead to the possible identification of unique stromal derived growth factors. The latter type of growth factors could potentially be utilized in the therapy of myelodeficiency states or in attempts to induce leukemic cell differientiation while a fuller understanding of the regulation of hemolymphopoiesis may impact upon diseases such as aplastic anemia and leukemia and on chemotherapy induced cytopenias.